A Stabilizing Influence: CAL PDZ Inhibition Extends the Half‐Life of ΔF508‐CFTR

Abstract

Recycling lohnt sich! Die am häufigsten auftretende Mutation bei Mukoviszidose verhindert die Reifung und beschleunigt den Abbau des Ionenkanals CFTR. Ein Stabilisator wird vorgestellt, der eine für den CFTR‐Abbau verantwortliche PDZ‐Domäne blockiert. Der Hemmstoff iCAL36 verlängert die Halbwertszeit des Chloridkanals in bronchialen Epithelzellen. Er ergänzt außerdem die Aktivität eines Faltungskorrektors und erfüllt damit eine Voraussetzung für kombinierte Mukoviszidosetherapien.

Disabled-2 Protein Facilitates Assembly Polypeptide-2-independent Recruitment of Cystic Fibrosis Transmembrane Conductance Regulator to Endocytic Vesicles in Polarized Human Airway Epithelial Cells

“…Plates were allowed to equilibrate 15 min at 24°C before measurement. Fitting was performed as described (13).…”

“…Recent studies have shown that the plasmamembrane half-life and cell-surface abundance of CFTR can be stabilized by inhibition of the CFTR-associated ligand CAL or by depletion of the ubiquitin ligase c-Cbl (13,14). Although several proteins involved in the uptake process have been identified (15), their roles are incompletely defined in polarized airway epithelial cells.…”

Reduced PDZ Interactions of Rescued ΔF508CFTR Increases Its Cell Surface Mobility

“…In the Golgi, modulation of the function or abundance of PDZ-domain containing proteins has been shown to correct ⌬F508CFTR trafficking (10,22,23). Similarly, EBP50 has been implicated in r⌬F508CFTR biosynthetic processing.…”

Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) Increases the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Airway Epithelial Cells by Phosphorylating Shank2E Protein

“…We and others have shown that plasma membrane abundance of CFTR is regulated by a number of PDZ proteins, including NHERF1/EBP50, NHERF2, and CFTR-associated ligand (1,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). A common feature of these proteins is the presence of a PDZ (PSD-95, Dlg, ZO-1) domain, a protein-protein interaction module that engages the C terminus of CFTR.…”